A variety of neurodegenerative disorders (e.g., Alzheimer's disease (AD)) are characterized by somal and neuritic degeneration in select brain regions. The fundamental mechanisms underlying neurodegeneration in these diseases are not well understood but remain an area of intense interest. Historically, experimental elucidation of relevant mechanisms has logically focused upon the neuronal cell body. Equally important, but nonetheless largely ignored, are degenerative events occurring in neurites. Mechanistically, neither the relative vulnerability of neurites to degenerative stimuli nor the relevant pathways driving neurite degeneration are understood. Since the brain's neuronal cell bodies and distal neuritic processes are separated by long distances, these two cellular compartments by definition must be exposed and respond to different microenvironments. In the AD brain for example, microenvironments will vary in their ability to sustain neuronal viability, with specific regions being characterized by a variety of degenerative stimuli (e.g., beta-amyloid accumulation, excitotoxic and oxidative stress inflammation). In this application, we propose that neurites exposed to such local toxic microenvironments will exhibit focal degenerative responses. Accordingly, we propose to study pathways that contribute to local neurite degeneration. Specifically, we will test the hypothesis that mechanisms of apoptosis classically associated with death in the cell body compartment also may be operative locally in spatially separated neurite compartments. Initially, we will use primary neuronal cultures to define degenerative parameters induced by various stimuli (both apoptotic and necrotic) known to cause cell death. We then will utilize a modified-Campenot chamber to evaluate the defined degenerative parameters in neuron cultures in which only the neuritic compartment is exposed to the toxic environment. Using this approach, we will study neuritic and somal mechanisms of degeneration after selective insult. These studies will include an analysis of caspase dependence, upstream pathways, and the cytoskeletal and synaptic proteins targeted in neurites. Further, we use this paradigm to examine how neuritic degeneration is modulated by over-expression of factors known to inhibit apoptotic cell death (e.g.,Bcl-2, CrmA) or promote AD pathology and perhaps vulnerability to cell death (e.g., AD-associated mutations in APP and presenilins). The studies proposed in this application will provide new and basic biological findings potentially relevant to a wide array of normal and pathological events involving synaptic remodeling and neurite degeneration.